In a retrospective observational cohort study testosterone therapy was associated with decreased mortality in men with low testosterone levels compared with no testosterone treatment

This observational, retrospective cohort study based on a clinical database that included seven Veteran Affairs medical centres in the US was the first to examine the association between testosterone treatment and mortality in men with low testosterone levels.1 Mortality was compared in testosterone-treated compared with untreated hypogonadal men, using appropriate statistical models adjusted for age, diabetes and coronary heart disease. Testosterone formulations included intramuscular injections (88.6%), patch (9.1%) or gel (2.3%). The cohort included 1031 men aged >40 (mean 62) years with low total testosterone levels ≤8.7 nmol/L (250 ng/dL) at study entry, no history of prostate cancer, who were assessed in 2001–2002 and followed-up until the end of 2005 (mean follow-up time 40.5 months).1

Mean body mass index (BMI) was 32.0 kg/m2, and mean total testosterone level was 6.3 nmol/L (181 ng/dL). There was a high degree of medical comorbidity in the cohort; a mean of 6.7 pharmacologically-treated medical conditions, including diabetes (38%), sexual dysfunction (36%) and coronary heart disease (21%). There was an association between lower testosterone levels and higher medical comorbidity (p=0.037).

Testosterone treatment continued to be associated with decreased mortality in secondary analyses and after sensitivity analysis

Although there was no significant effect modification by age, diabetes or cardiovascular disease, testosterone treatment appeared to be associated with greater mortality reduction in younger men (age <60 years), diabetic men and men without coronary heart disease

During the study, 1.6% of testosterone-treated men and 2.0% of untreated men were diagnosed with incident prostate cancer (p=0.68).

What is known

Low testosterone levels, common in older men, are associated with a range of adverse outcomes, including diabetes, obesity, cardiovascular events, loss of muscle mass and strength, osteoporosis and diminished libido.2,3 It has been reported that there is an (approximately two-fold) increase in mortality in men with low testosterone, compared with men with normal testosterone levels,4 which has been confirmed by most,5-8 but not all9,10 other studies. The use of testosterone replacement therapy has increased markedly in recent years, particularly in the US.11 Therefore it is important to clarify the risks and benefits of testosterone treatment in the health of older men with low testosterone levels.

A number of studies have shown beneficial effects for testosterone treatment in older men, including improvements in muscle mass and strength and increased bone mineral density, insulin sensitivity and libido.12-15 Nevertheless, ongoing concerns about prostate cancer incidence or mortality linger, and there was a recent unexpected finding when a trial in frail, elderly men was discontinued after a greater occurrence of cardiovascular events in testosterone-treated men.16 However, another study in a similar population of frail elderly men found no increased cardiovascular risk,14 and a systematic review and meta-analysis found no increased cardiovascular risks with testosterone treatment.17

What this study adds

This retrospective observational cohort study showed that testosterone replacement therapy significantly decreased mortality in the cohort of men with low total testosterone levels and a high level of chronic medical morbidity.1

The limitations of observational study design mean that these results should be viewed cautiously. However, despite these and other potential study limitations, the study had a number of significant strengths. The study was the first to specifically examine the association between testosterone treatment and mortality in middle-aged and older men with low testosterone levels, and the threshold for inclusion in the study required clearly low testosterone levels, increasing the likelihood that men in the study had symptomatic and clinically significant androgen deficiency. This is also one of the first large studies to examine testosterone treatment in men with high medical morbidity. Such men may be more susceptible to harm or benefit from testosterone treatment.

While the results cannot be interpreted as demonstrating beneficial effects of testosterone treatment or establishing a causal relationship between testosterone treatment and reduced mortality, they should stimulate further investigation of the effects of testosterone treatment on the health of older men. The gold standard to examine any such causal relationship would be a large-scale, randomized, double blind, placebo-controlled trial.